1. Field of Invention
This invention relates to triphenylpropanamide compounds which are useful in treating inflammations but which do not demonstrate the side effects normally associated with other anti-inflammatory treatments such as glucocorticoids This invention also relates to methods for making and using the compounds of the invention.
2. Prior Art
Glucocorticoids are the only agents which reduce all the symptoms that are manifested in chronic adrenocortical disorder and hyperfunction, allergies, rheumatoid arthritis, lupus, inflammatory bowel disease, pneumonia, bronchial asthma, hematological disorders, dermatitis and eczema. Glucocorticoids also reduce immunological response in organ transplants. The undesired side effects of these agents include hypertension, atherosclerosis, diabetes, hyperglycemia, bone thinning and electrolyte imbalance.
Mechanistically, glucocorticoids bind to the glucocorticoid receptor (GR) on the surface of leukocytes and the resulting glucocorticoid -GR complex migrates into the cell nucleus. There, the complex interacts with transcription factor AP-1 (activating protein-1), inhibiting its induction of genes that produce inflammatory cytokines and collagenase, thereby repressing the inflammatory process. However, the complex also activates GRE (glucocorticoid response element), a transcriptional activator of genes which are responsible for the undesirable side effects mentioned heretofore. The most desirable anti-inflammatory medication would inhibit AP-1 without activating GRE.
Steroids, such as dexamethasone and prednisone have been found to exhibit potent antiinflammatory activity, but also exhibit the previously-mentioned side effects.
Heretofore, there has been no antiinflammatory agent found which does not cause side effects. Thus, new chemical agents are needed which would have the desired antiinflammatory effect without causing the side effects mentioned above.
Prior art compounds which relate to the triphenylcyclopropyl and triphenylpropyl compounds of the invention are as follows: U.S. Pat. No. 3,941,833 (Gognaco) describes certain amino derivatives of 2,2diaryl-cyclopropane. They are described as being useful for the treatment of disorders of the cardiovascular system. They are intended for systemic use. There is no indication in this patent that such compounds can or should be administered topically. Nor is there any indication that such compounds would be useful for treating inflammation of the skin.
Gilbert, et al. in J. Med. Chem. 1983, 26, 693-699 report triphenylpropylidene amines and nitrites as inhibitors of prostaglandin synthetase
Blank et al. in J. Med. Chem. 1969, 12, 873-876 describe the inhibition by 2,3,3-triphenylpropylamines of the biosynthesis of aldosterone without altering deoxycorticosterone or corticosterone levels.
Schultz et al. in J. Med. Chem. 1967, 10, 717-724 describe diphenylpropanamides which are hypocholesteremic in rats and inhibit penicillin excretion in dogs.
Burch et al. in Proc. Natl. Acad. Sci. USA 1991, 88, 355-359 describe fluorenyl propanamides which inhibit localized inflammatory reactions in mice.
German Patent No. 2,726,993 (Gognaco) describes 1-substituted 2,2-diphenylcyclopropanes. The patent indicates that they are useful as vasodilators and blood pressure lowering agents. They are intended for systemic use. There is no indication in this patent that such compounds can or should be administered topically. Nor is there any indication that such compounds would be useful for treating inflammation of the skin.
Belgian patent No. BE 855689 (Hexachemie S. A. Fr.) describes 2,2-diphenylcyclopropylmethylamides with vasodilator activity.
Precigoux, et al. describe the compound 4,4xe2x80x2-(3-Acetemido-2-phenylpropylidene) diphenol diacetate in Acta Crystallogr., Sect. C: Cryst. Struct. Commun., C41 (8), 1985, pp. 1244-1246.
Falkenstein et al. describe certain phenylaziridine compounds in xe2x80x9cSingle electron transfer versus nucleophilic ring opening in reactions of cis-trans pairs of activated 2-phenylaziridines. Strong influence of nitrogen pyramid for N-benzoylaziridines.xe2x80x9d, J. Org. Chem., 1993, 58, pp. 7377-7381.
Stamm et al. describe other aziridines in xe2x80x9cReactions with aziridines.53. Arene hydrides. 9. Intermediate substitution in the formation of a benzylic anion by an aromatic radical anion as observed with 1-benzoyl-2-phenylaziridine.xe2x80x9d Chem. Ber., 1990, 123, pp. 2227-2230. Stamm et al. also described related aziridine structures in xe2x80x9cReductive ring opening of N-benzoylaziridine by anthracene hydride (anion of 9,10-dihydroanthracene) via base-induced fragmentation of the intermediate carbonyl adduct.xe2x80x9d J. Org. Chem., 1989, 54, pp. 1603-1607. However, none of these publications describe the structures of this invention nor do they indicate that such compounds would be useful in treating inflammation.
Therefore, it is an object of this invention to provide one or more compounds capable of treating inflammatory diseases.
It is a further object of this invention to provide compounds capable of treating inflammatory diseases without causing side effects similar to those caused by glucocorticoids.
It is yet another object of this invention to provide a method of making compounds for treating inflammatory diseases.
Another object of this invention is to provide a method of treating inflammatory diseases in mammals by administration of the compounds of this invention.
This invention relates to novel non-steroidal small molecule organic compounds that exhibit the beneficial therapeutic properties of glucocorticoids, that may be free of glucocorticoid-like side effects, and which may have a high affinity for the human glucocorticoid receptor (hGR). The compounds of this invention have the following structure (I): 
wherein X, R1, R2, R3, R4, R5, W, Y and Z are as defined hereinafter.
These compounds are useful in treating inflammatory diseases in humans and other mammals. The compounds of the present invention may also be useful in the treatment of other disorders, such as chronic adrenocortical disorder and hyperfunction, allergies, rheumatoid arthritis, lupus, use as immunosuppressants in organ transplant, pneumonia, bronchial asthma, hematological disorders, dermatitis and eczema. The present invention is also directed to pharmaceutical compositions containing the compounds of formula I and methods of treating inflammation and other conditions employing such compounds.
As used herein unless otherwise noted, alkyl and alkoxy, whether used along or as part of a substituent group, include straight and branched chains. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Alkoxy radicals are oxygen ethers formed from the previously described straight or branched chain alkyl groups. Of course, if the alkyl or alkoxy substituent is branched there must be at least three carbon atoms in the group.
The term xe2x80x9carylxe2x80x9d as used herein along or in combination with other terms indicates aromatic hydrocarbon groups such as phenyl or naphthyl. The term heteroaryl means aromatic groups, incorporating as part of the aromatic ring, 1 or 2 hetero atoms selected from any of S, O, or N. With reference to substituents, the term xe2x80x9cindependentlyxe2x80x9d means that when more than one of such substituent is possible such substituents may be the same or different from each other.
The present invention is directed to compounds of the general formula I: 
X may be a single bond or is chosen from hydrogen, sulfur or NR5; wherein R5 is selected from the group consisting of: hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; phenyl, in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl (C2-C6), lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido, or nitrile; phenyl lower alkyl in which said phenyl group is substituted with hydrogen or with from one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile. X may further be selected from xe2x80x94(CH2)n wherein n is an integer from 1 to 3; xe2x80x94HCxe2x95x90CHxe2x80x94; and xe2x80x94CHxW wherein W may be oxygen, sulfur or NR5. Of course when X is hydrogen, it does not represent a connection between the phenyl rings;
wherein R1 is from one to three substituent groups each selected from the group consisting of lower alkyl (C2-C6), lower alkoxy, hydroxy, halogen such as chlorine, fluorine, iodine or the like, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile;
wherein R2 is a phenyl group in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl(C2-C6), lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile; or a heteroaromatic ring such as substituted- or unsubstituted thiophene, furan, pyrrole, pyridine, or the like;
wherein Y is xe2x80x94CH2xe2x80x94 or hydrogen;
wherein R3 is chosen from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; phenyl in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile; phenylloweralkyl in which said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile;
wherein Z is selected from the group consisting of carbonyl; carboxy; carbonylamino; or sulfone; and
wherein R4 is straight- or branched-chain alkyl having from 2 to 12 carbon atoms; phenylloweralkyl in which said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile; a heteroaromatic ring such as substituted-or unsubstituted thiophene, furan, pyrrole, pyridine, or the like or a heteroaromatic ring connected by a lower alkyl chain wherein said heteroaromatic ring is chosen from substituted-or unsubstituted thiophene, furan, pyrrole, pyridine or the like. When X is hydrogen, S or NR5, R4 may be phenyl wherein said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile.
Preferably, the compounds of this invention have formula (I) above wherein X is hydrogen and Y is hydrogen. Also preferable are the compounds of this invention wherein R1 is selected from the group consisting of hydrogen and halogen. More preferably, R1 is fluorine.
More preferably, the compounds of this invention have formula (I) above wherein X is hydrogen, Y is hydrogen, R1 is selected from the group consisting of hydrogen and halogen and R2 is selected from the group consisting of phenyl, halophenyl, or methylenedioxyphenyl. Most preferably, R1 is fluorine or hydrogen and R2 is 4-chlorophenyl, 4-lodophenyl or 3,4-methylendioxyphenyl.
Also preferable are compounds of formula (I) wherein X is hydrogen, Y is hydrogen, R1 is selected from the group consisting of hydrogen and halogen, R2 is selected from the group consisting of phenyl, halophenyl, or alkoxyphenyl and R3 is selected from the group consisting of hydrogen and lower alkyl. Most preferably, R3 is hydrogen.
Another preferable group of compounds of formula (I) are those wherein X is hydrogen, Y is hydrogen, R1 is selected from the group consisting of hydrogen and halogen, R2 is selected from the group consisting of phenyl and halophenyl, R3 is selected from the group consisting of hydrogen and lower alkyl and Z is carbonyl. Preferably, R4 is selected from the group consisting of straight-chain alkyl, phenyllower alkyl and heteroaromatic lower alkyl. Even more preferably R4 is a heteroaromatic lower alkyl group. Most preferably, R4 is 2-thiophenemethylene or 4-chlorophenylmethylene.
The compounds of this invention are useful in treating inflammatory diseases such as rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, dermatitis, and eczema. They may also be therapeutically beneficial in the treatment of other disorders including lupus, chronic adrenal disorder and hyperfunction, allergies, pneumonia, bronchial asthma, hematological disorders and as immunosuppressants in organ transplant. They may be administered topically or systemically.
The compounds of this invention have been found to bind to the hGR. However, because they differ in structure from glucocorticoids, they appear to bind selectively to the hGR, without binding to DNA and activating the GRE. This results in a potentially much lower incidence of side effects, and, consequently, longer periods of administration with greater overall efficacy and relief.
The compounds of this invention are optically active. The beneficial therapeutic activity may reside with either enantiomer or they may be most active and advantageously utilized in racemic mixtures.
Examples of particularly preferred compounds include: 98, 29, 33, 72, 90, 96, 84, 80, 47, 97, 123, 127, 128, 132, 140, 141, 145, 147, 150, 153, 165, 167, 173, 174, 175, 176, 177, 178, 179, and 180. Exemplary compounds are as follows:
N-(2-thiophene)acetyl-2, 3, 3-triphenylpropylamine.
N-(5-methylthiophene)acetyl-2-phenyl-3, 3-bis (4-fluorophenyl)propylamine.
N-(3-indolyl) acetyl-2, 3, 3-triphenylpropylamine.
N-(2-carbonyl-5-methylthiophene)-2-(9H-fluoreny-9-yl)-2-phenylethylamine.
N-(2chlorophenyl)acetyl-1, 2, 2-triphenylcyclopropylmethylamine.
N-(2-thienyl)carbonyl-1, 2, 2-triphenylcyclopropylmethylamine.
N-(phenyloxy)carbonyl-1, 2, 2-triphenylcyclopropylmethylamine.
N-(4-chlorophenyloxy)carbonyl-1, 2, 2-triphenylcyclopropylmethylamine.
N-(2-pyridine)acetyl-2-(3, 4methylenedioxyphenyl)-3, 3-diphenylpropylamine.
N-(4-n-butoxyphenyl)acetyl-2-(3, 4-methylenedioxyphenyl)-3, 3-diphenylpropylamine.
N-(2, 4-difluorophenyl)acetyl-2-(3, 4-methylenedioxyphenyl)-3, 3-diphenylpropylamine.
N-(2-thiophene)carbonyl-2-(3, 4-methylenedioxyphenyl)-3, 3-diphenylpropylamine.
N-(3-cyanophenyl)acetyl-2-(3, 4-methylenedioxyphenyl)-3, 3-diphenylpropylamine.
N-(2, 4-difluorophenyl)carbonyl-2-(3, 4-methylenedioxyphenyl)-3, 3-diphenylpropylamine.
N-(4-fluorophenyl)acetyl-2-(3, 4-methylenedioxyphenyl)-3, 3-diphenylpropylamine.
N-(4, 5-dichlorophenyl)carbonyl-2-(3, 4-methylenedioxyphenyl)-3, 3-diphenylpropylamine.
N-(3-methylphenyl)acetyl-2-(4trifluoromethylphenyl)-3, 3-diphenylpropylamine.
N-(phenyl)acetyl-2-(4trifluoromethylphenyl)-3, 3-diphenylpropylamine.
N-(5-chloro-2-benzothiophene)acetyl-2-(4-trifluoromethylphenyl)-3, 3-diphenylpropylamine.
N-(2, 4-difluorophenyl)carbonyl-2-(4-trifluoromethylphenyl)-3, 3-diphenylpropylamine.
N-(4-trifluoromethylphenyl)acetyl-2-(4-trifluoromethylphenyl)-3, 3-diphenylpropylamine.
N-(phenyl)acetyl-2-(4-trifluoromethylphenyl)-3, 3-diphenylpropylamine.
N-(4-fluorophenyl)acetyl-2-(4-iodomethylphenyl)-3, 3-diphenylpropylamine.
N-(3, 5-bis-tri fluorophenyl)carbonyl-2-(4-iodomethylphenyl)-3, 3-diphenylpropylamine.
N-(4- chiorophenyl)carbonyl-2-(4-iodomethylphenyl)-3, 3-diphenylpropylamine.
N-(3, 4-dichlorophenyl)carbonyl-2-(4-iodomethylphenyl)-3, 3-diphenylpropylamine.
N-(2-fluorophenyl)carbonyl-2-(4-iodomethylphenyl)-3, 3-diphenylpropylamine.
N-(2-fluorophenyl)carbonyl-2-(4-iodomethylphenyl)-3, 3-diphenylpropylamine.
N-(4-fluorophenyl)carbonyl-2-(4-iodomethylphenyl)-3, 3-diphenylpropylamine.
N-(4-trifluoromethylphenyl)carbonyl-2-(4-iodomethylphenyl)-3, 3-diphenylpropylamine.
N-(3, 5-bistrifluoromethylphenyl)carbonyl-2-(4-iodomethylphenyl)-3, 3-diphenylpropylamine.
N-(2-thiophene)carbonyl-2-(4-iodomethylphenyl)-3, 3-diphenylpropylamine.
N-(5-methyl-2-thiophene)carbonyl-2-(4-iodomethylphenyl)-3, 3-diphenylpropylamine.
N-(4-chlorophenyl)carbonyl-2-(3, 4-methylenedioxyphenyl)-3, 3-diphenylpropylamine.
N-(2-propyl)carbonyl-1, 2, 2-triphenylcyclopropylmethylamine.
The compounds of this invention may also include the respective hydrates of compounds specifically identified herein.
The compounds of formula I may be prepared according to the following reaction schemes.
Reaction Scheme 1 displays a method of making the compounds of formula I, where R1-R5, W, X, Y and Z are as defined above. Treatment of a suitable substituted or unsubstituted diphenyl methyl-, fluorenyl-, or 10,11-dihydro-5H-dibenzo[1,d]cyclohepten4-yl chloride or bromide with an aryl- or heteroaryl acetonitrile using n-BuLi and the like or phase-transfer conditions, afford nitrile intermediates of structure A. Reduction of A with LAH, NaBH4/BH3 and the like leads to the formation of amines C. Treatment of structure A with methylene chloride in the presence of potassium amide/liquid ammonia leads to the formation of structure B. Reduction of the nitrile group of structure B with LAH, NaBH4/BH3 and the like leads to an amine of structure D. By reacting C or D with acid chlorides as set forth below in Scheme I in combination with bases such as NaOAc and the like, organic acids in combination with activating agents such as 1,1xe2x80x2-carbonyldiimidazole and the like, sulfonyl chlorides, chloroformates, isocyanates, isothiocyanates, or a suitable organic sulfonyl chloride, compounds of structure I are obtained. Optionally, nitrites of structure A, when treated with diisobutylaluminum hydride (DiBAL), are converted to aldehydes of structure E. Treatment of E with Rink resin affords resin-bound imines of structure F which are reduced with sodium triacetoxy borane to resin-bound imines of structure G. Treatment of G with an appropriate acid in the presence of O-(7-azabenzotriazol-1-yl)-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium hexafluorophosphate (hereinafter referred to as xe2x80x9cHATUxe2x80x9d) and diisopropylethylamine (DIEA) affords compounds of structure I. Compounds of structure I may also be prepared by the reaction of amines of structure H with appropriate carboxylic acids in the presence of resin-bound 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide which is prepared from 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and Merrifield resin. 
To prepare the pharmaceutical compositions of this invention, one or more compounds or salts thereof of the invention, as the active ingredient, is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus for liquid oral preparations, such as for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations, such as, for example, powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, though other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions herein will preferably contain per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, from about 50 to about 100 mg of the active ingredient, although other unit dosages may be employed. The compounds of this invention may also be applied or utilized topically. If the delivery parameters of the topically active pharmaceutical or cosmetic agent so require, the topically active composition of this invention may preferably be further composed of a pharmaceutically or cosmetically acceptable vehicle capable of functioning as a delivery system to enable the penetration of the topically active agent into the skin. In alternative embodiments, the topically active pharmaceutical or cosmetic composition may be optionally combined with other ingredients such as moisturizers, foaming agents, cosmetic adjuvants, anti-oxidants, surfactants, foaming agents, conditioners, humectants, fragrances, viscosifiers, buffering agents, preservatives, and the like in an amount which will not destroy the active ingredient in order to produce cosmetic or pharmaceutical products.
The topically active pharmaceutical or cosmetic composition should be applied in an amount effective to treat inflammation of mammalian skin. As used herein xe2x80x9camount effectivexe2x80x9d shall mean an amount sufficient to ameliorate inflammation of mammalian skin. A composition containing 0.001-10.0% of active agent is applied to the skin surface when amelioration of an inflammatory condition is desired. Preferably, a composition containing upon a square cm of skin surface, from about 2 xcexcl/cm2 to about 8 xcexcl/cm2 of topically active agent is present when amelioration of an inflammatory condition is desired. 0.05-5.0% of active agent is applied to the skin surface such that, based upon a square cm of skin surface, from about 2 xcexcl/cm2 to about 8 xcexcl/cm2 of topically active agent is present when amelioration of an inflammatory condition is desired.